On February 23, 2018, Kyowa Hakko Kirin Co. Ltd and its partner Ultragenyx Pharmaceutical Inc. announced that a conditional marketing authorization had been granted in the European Union (EU) for burosumab (Crysvita) as a treatment for X-linked hypophosphatemia in children 1 year of age and older, and adolescents with growing skeletons. Burosumab is a human IgG1 monoclonal antibody that binds to and inhibits the activity of fibroblast growth factor 23, thereby reducing loss of phosphate from the kidney and other metabolic abnormalities, and ameliorating bone changes that are a hallmark of the disease. The marketing approval in the EU is the first for burosumab. A biologics license application is undergoing review by the US Food and Drug Administration (FDA), and an action on the application is expected by April 17, 2018.

On February 27, 2018, Roche announced that emicizumab (Hemlibra®) had been approved in the EU for routine prophylaxis of bleeding episodes in people with hemophilia A with factor VIII inhibitors. Emicizumab, a bispecific IgG4 mAb targeting Factors IXa and X that originated at Chugai Pharmaceutical Co. Ltd., was approved by the FDA on November 16, 2017.

On March 2, 2018, Biogen and AbbVie announced the voluntary worldwide withdrawal of marketing authorizations for ZINBRYTA® (daclizumab) for relapsing multiple sclerosis (MS). The withdrawal coincides with an urgent review by the European Medicines Agency (EMA) of inflammatory brain disorder in 8 patients, and follows a 2017 review by EMA of reports of liver injury. Due to the risk of serious liver damage, EMA limited use of Zinbryta to MS patients who had tried at least two other disease modifying treatments and could not be treated with any other such treatments. ZINBRYTA® had been marketed in the EU, US, Switzerland, Canada and Australia.

Ocrelizumab (OCREVUS), a humanized IgG1 mAb targeting CD20, is the first drug approved by the FDA for PPMS. Ocrelizumab was granted FDA’s Breakthrough Therapy and Fast Track designations, and its application received priority review. A marketing application for ocrelizumab for the treatment of relapsing multiple sclerosis and primary progressive multiple sclerosis (MS) is being reviewed by the European Medicines Agency. The marketing applications are based on positive results from three Phase 3 studies, OPERA I (NCT01247324), OPERA II (NCT01412333), and ORATORIO (NCT01194570). Identical in their study design, OPERA I and OPERA II evaluated the efficacy and safety of 600 mg ocrelizumab intravenously (IV) administered every six months compared with 44 mg interferon beta-1a (Rebif®) subcutaneously administered 3 times per week in 1,656 people with relapsing forms of MS. Compared with Rebif®, ocrelizumab showed superior efficacy in reducing annualized relapse rates and disability progression sustained for at least three and for at least six months. The ORATORIO study evaluated the efficacy and safety of 600 mg ocrelizumab administered by IV infusion every six months compared with placebo in 732 people with primary progressive MS. Compared to patients who received placebo, patients who received ocrelizumab in this study showed significant reductions in disability progression sustained for at least three and for at least six months, as well as in other measures of progressive disease.

Dupilumab (Dupixent®), an anti-IL-4Ra IgG4 mAb, was granted Breakthrough Therapy designation for moderate-to-severe atopic dermatitis, and the biologics license application was granted a priority review by FDA. The safety and efficacy of Dupixent were established in three placebo-controlled clinical trials with a total of 2,119 adults with moderate-to-severe atopic dermatitis not adequately controlled by topical medication(s). A marketing application for dupilumab is being reviewed by the European Medicines Agency.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review in the EU or US. As of March 28, 2017, marketing applications for a total of 10 antibody therapeutics that have not been approved in any country are undergoing review in the EU or US. In addition, marketing applications for sarilumab, which is approved in Canada, and gemtuzumab ozogamicin, which was FDA approved in 2000 and subsequently withdrawn from the US market, are undergoing review in the EU and US.

First marketing applications were recently submitted for two novel antibody therapeutics, ocrelizumab and inotuzumab ozogamicin, intended as treatments for multiple sclerosis (MS) and CD22-positive acute lymphoblastic leukemia (ALL), respectively. Applications for ocrelizumab (OCREVUS), a humanized IgG1 antibody that targets CD20, as a treatment of relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) are undergoing regulatory review by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). No products are currently approved for both forms of MS. A priority review designation has been granted by FDA, and a first action on ocrelizumab’s biologics license application (BLA) is thus expected by December 28, 2016. The marketing applications are based on positive results from two identical Phase 3 studies (OPERA I and OPERA II) in people with RMS and the Phase 3 ORATORIO study in people with PPMS. All primary and key secondary endpoints were met in these three studies.

The antibody-drug conjugate inotuzumab ozogamicin targets CD22, an antigen found on the surface of cancer cells in most ALL patients. Results of a Phase 3 study evaluating the safety and efficacy of inotuzumab ozogamicin compared with investigator-choice chemotherapy in 326 adult patients with relapsed or refractory CD22-positive ALL were recently published in the New England Journal of Medicine. Improvements over chemotherapy on a number of measures, including complete hematologic remission and progression-free survival, were observed in this study. A marketing application for inotuzumab ozogamicin is undergoing review by the EMA; a BLA submission is likely. Inotuzumab ozogamicin received Breakthrough Therapy designation for ALL from FDA, and priority review of applications is a benefit of the designation, which suggests that an approval by FDA is thus possible by the end of 2016.

The Antibody Society maintains a comprehensive table of approved antibody therapeutics and those in regulatory review (currently 8 mAbs) in the European Union and United States. The antibody target, format and year of first approval are included. Please log in to access the table, located in the Members Only section.

On May 27, 2016 the Food and Drug Administration (FDA) approved daclizumab (Zinbryta®) for the treatment of adults with relapsing forms of multiple sclerosis (MS). The product, which targets interleukin-2 receptor alpha chain (CD25), is manufactured using a high-yield process. Daclizumab (Zenapax®) was first approved in 1997 for the prevention of organ transplant rejection. While the two products have the same amino acid sequence, Zinbryta has a different glycosylation pattern and reduced antibody-dependent cytotoxicity compared to Zenapax. Zinbryta’s approval was based in part on the results of the Phase 3 DECIDE study (NCT01064401) of Zinbryta versus interferon β 1a (Avonex®) in patients with relapsing-remitting MS. In this study, patients administered Zinbryta experienced fewer clinical relapses than those who received Avonex (annualized relapse rate 0.22 vs. 0.39; 45% lower rate with Zinbryta; P<0.001). Due to serious safety risks, FDA has included a boxed warning on the product label, and it is available only through a restricted distribution program under a Risk Evaluation and Mitigation Strategy.

Another antibody therapeutic, ocrelizumab, has been evaluated in a Phase 3 study of patients with primary progressive multiple sclerosis (PPMS). The antibody targets CD20 on B cells, which are implicated in the inflammatory and neurodegenerative processes of MS. Ocrelizumab was granted FDA’s Breakthrough Therapy Designation for PPMS, which is a debilitating form of MS characterized by steadily worsening symptoms. PPMS patients typically do not experience distinct relapses or periods of remission. Currently, no treatments are approved for treatment of the disease. In the pivotal Phase 3 ORATORIO study, treatment with ocrelizumab significantly reduced disability progression and other markers of disease activity compared with placebo. Ocrelizumab is also undergoing evaluation in Phase 3 studies of patients with relapsing-remitting forms of the disease. Genentech plans to submit a marketing application for ocrelizumab as a treatment for MS in 2016. If an application is submitted to FDA by the end of June and receives a priority review, which is a benefit of the Breakthrough Therapy Designation, then ocrelizumab could be approved for marketing in the US by the end of 2016.